Anorexia is a debilitating manifestation of many malignancies. The etiology of cancer anorexia is poorly understood, and effective treatment options are limited. To investigate the role of central melanocortin receptor signaling in the pathogenesis of cancer anorexia, we assessed the effects on food intake of the melanocortin receptor antagonist SHU9119 administered into the third cerebral ventricle of Lobund-Wistar rats that were anorexic from prostate cancer. In anorexic tumor-bearing rats, daily treatment with SHU9119 (0.35 nmol, intracerebroventricularly) increased food intake from 71 +/- 3% to 110 +/- 6% of preanorectic baseline and caused significant weight gain (13 +/- 5 vs. 5 +/- 1 g/3 d, SHU9119 vs. baseline in tumor-bearing rats). In control rats pair-fed to the intake of tumor-bearing animals, SHU9119 was ineffective at increasing food intake. The specificity of the SHU9119 feeding response was assessed using two other orexigenic peptides, NPY and the novel hormone ghrelin. Treatment of tumor-bearing rats with intracerebroventricular ghrelin (10 microg) increased food intake, but the effect was blunted relative to that in controls. Intracerebroventricular injections of NPY (1 microg) also failed to reverse anorexia in tumor-bearing rats. Because SHU9119 completely reverses cancer anorexia in this model, whereas ghrelin and NPY do not, increased central nervous system melanocortin signaling is implicated in the pathogenesis of this disorder. This suggests that new targets for the treatment of cancer anorexia may be found in the melanocortin pathways.